Our overall objective is to obtain a better understanding of carbohydrates and fat metabolism during prolonged exercise. We have preliminary results that suggest that elevation of plasma fatty acids in rats running on a treadmill partially inhibits glucose uptake and glycogen breakdown in the red types of skeletal muscles. One of our major aims is to follow up this finding with studies of the regulatory mechanisms by which elevation of FFA levels inhibits carbohydrate utilization in red skeletal muscle during exercise. These studies will be conducted on (a) intact rats running on a treadmill, and (b) perfused working skeletal muscle in which the concentration of substrates can be carefully controlled. A second aim is to obtain information regarding why glycogen appears to be an indispensable substrate for skeletal muscle during prolonged heavy exercise. This problem will be investigated in perfused, working muscle, and in a reconstituted system containing mitochondria and certain cytoplasmic enzymes. A third aim is to elucidate the mechanisms by which an elevation of plasma FFA slows down the rate of glycogen depletion in liver during exercise. This problem will be studied in rats exercised on a treadmill.